Hornung Lab - Research
- Nucleic acid sensors
- Genome Engineering
Inflammasomes constitute a family of cytosolic sensors that can directly detect microbial molecules but also indirectly sense damage by detecting the perturbation of cellular homeostasis. Within recent years a lot of progress has been made in the characterization of inflammasome components and their pivotal role as surveillance machineries in the context of infection. Besides, it has become evident that many non-communicable diseases are triggered or perpetuated by inflammasomes and several studies have uncovered the great therapeutic potential of targeting these pathways. In that respect, inflammasomes have also become a prime focus for the development of novel anti-inflammatory therapies.
The minimal inflammasome signaling unit consists of a sensor protein and pro-caspase-1 that gets recruited to this sensor upon activation. Most inflammasomes, however, make use of the additional adapter protein ASC that serves to introduce a threshold-like signaling behavior and to amplify the response. The sensor protein itself often encodes for an oligomerization function that is engaged upon activation. This oligomerization of the sensor serves to form a seed-like structure that is required to initiate the assembly of a filamentous signal hub by the adapter protein ASC, which in turn recruits pro-caspase-1. In the case of NLR (nucleotide-binding domain and leucine-rich repeat-containing) proteins, it is the central NACHT domain that serves this function. Upon recruitment to the inflammasome complex, pro-caspase-1 is activated so that it can mature its substrates, such as the highly pro-inflammatory cytokine pro-IL-1β. Furthermore, caspase-1 cleaves the pore-forming molecule GSDMD, which triggers the lytic cell death of pyroptosis.
Next to its prominent role in processing of proinflammatory cytokine targets, caspase-1 also cleaves many other cytosolic proteins, the role of those is only starting to be understood. In our current projects we are mainly focusing on two inflammasome complexes: on the one hand, AIM2, a very specific sensor for cytosolic DNA and on the other hand NLRP3, a very important, yet up to now mechanistically poorly understood NLR sensor that responds to a large variety of cytoplasmic damage signals.
Using various complementary approaches, we are currently trying to understand their molecular mechanisms of activation and we aim at deciphering their functional roles at the cellular and organismic level in health and disease.
CARD8 inflammasome activation triggers pyroptosis in human T cells.
Linder A, Bauernfried S, Cheng Y, Albanese M, Jung C, Keppler OT, Hornung V.
EMBO J. 2020 Aug 25:e105071. doi: 10.15252/embj.2020105071. PMID: 32840892 [Epub ahead of print].
Inflammasome-Dependent Induction of Adaptive NK Cell Memory.
van den Boorn JG, Jakobs C, Hagen C, Renn M, Luiten RM, Melief CJ, Tüting T, Garbi N, Hartmann G, Hornung V.
Immunity. 2016 Jun 21;44(6):1406-21. doi: 10.1016/j.immuni.2016.05.008. Epub 2016 Jun 7. PubMed
Human Monocytes Engage an Alternative Inflammasome Pathway.
Gaidt MM, Ebert TS, Chauhan D, Schmidt T, Schmid-Burgk JL, Rapino F, Robertson AA, Cooper MA, Graf T, Hornung V.
Immunity. 2016 Apr 19;44(4):833-46. doi: 10.1016/j.immuni.2016.01.012. Epub 2016 Mar 29. PubMed
A Genome-wide CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) Screen Identifies NEK7 as an Essential Component of NLRP3 Inflammasome Activation.
Schmid-Burgk JL, Chauhan D, Schmidt T, Ebert TS, Reinhardt J, Endl E, Hornung V.
J Biol Chem. 2016 Jan 1;291(1):103-9. doi: 10.1074/jbc.C115.700492. Epub 2015 Nov 9. PubMed
The NLRP3 inflammasome renders cell death pro-inflammatory.
Gaidt MM, Hornung V.
J Mol Biol. 2017 Dec 1. pii: S0022-2836(17)30563-6. doi: 10.1016/j.jmb.2017.11.013. [Epub ahead of print] Review. PubMed
Alternative inflammasome activation enables IL-1β release from living cells.
Gaidt MM, Hornung V.
Curr Opin Immunol. 2017 Feb;44:7-13. doi: 10.1016/j.coi.2016.10.007. Epub 2016 Nov 11. Review. PubMed
Pore formation by GSDMD is the effector mechanism of pyroptosis.
Gaidt MM, Hornung V.
EMBO J. 2016 Oct 17;35(20):2167-2169. Epub 2016 Aug 29. No abstract available. PubMed